T cells: negative regulation and Tregs Flashcards
What does neg regulation involve
Receptors
Mechanisms
And cell types - like tregs
When does immune response contract
Within 10-14 days
Do not need clones anymore - post initial infection
Describe immune response contraction
After ag removed = most lymphocytes no longer needed = apoptosis
Tregs may also help quell responses by releasing inhibitory cytokines - help dampen immune response
Describe clonal contraction
Most newly generated b and T cells lost at end of primary immune response = lose clones after ag cleared most of effector cells no longer needed
Cells die by apoptosis
Name the 2 pathways for cell death via apoptosis
Intrinsic
Extrinsic
Describe intrinsic cell death pathway
Death by neglect
Il2Raplha and other cytokines receptors expression is transient = impermanent (il2 and il2Ralph gives cell survival signal)
Lack of signalling through receptors —> absence of survival signals —> cell apoptosis, cell programs own cell death
Describe extrinsic cell death pathway
Triggered by fas-fasL (fas expressed on T cell, and fasl expressed on ctl)
Involves ctls
Leads to apoptosis
Describe memory T cells
Respond with heightened reactivity -response to a subsequent explore to same antigen
Secondary response faster and more robust = more effective
What happens to the majority of effector T cells
At least 90% = die
Leaves behind antigen specific memory T cells - a few
Describe response process of infection, both primary and secondary infection
Primary infection = naive clonal expansion, effector T cells, contraction, then memory T cells
Secondary = same steps but faster and more robust, bc of memory T cells
= doesn’t go back to baseline = have memory T cells that can still exert effector function if meet same ag
(Reasoning for vaccines)
When does neg reg happen
At every step
Describe T cell activation neg reg
Ctla4 binds b7
What does ctla4 do - gen
Downregulates T cell activation, proliferation and survival
What does ctla4 do - binds to
B7.1/b7.2 with higher affinity than cd28
=shuts down signalling pathways, prevents excessive and uncontrolled immune responses - kepts it leveled
When is ctla4 induced
Expressed on surface T cells = Within 24 hours after activation
Peaks within 2-3 days post stimulation
Where is ctla4 found
As a protein intracelluarly —> phosphorylation allows it to be expressed on cell membrane
What type of regulation is ctla4
Post translational regulation - only expressed when T cell activated
What does ONE ctla4 bind
Can bind 2 b7 molecules = sequesters b7 and prevents biding to cd28
Bc ctla4 has higher affinity b7
What can ctla4 do in some cases
Can strip b7 molecules from apcs and remove them from apc surfaces
Endocytose it = clatrhin dependent
Compare cd28 and ctla4 expression
Cd28 = expressed by naive T cells at baseline
Surface expression ctla4 induced after activation of naive T cells —> after receiving signals 1 and 2
Describe how ctla4 prevents overgrowth of lymphocytes
Activated T cells less sensitive than naive T cells to stimulation by apcs =
Restricts il2 production
If an activated T cell meets match again = boosts but to prevent too much boosting/clones/overgrowth= express ctla4
Name the 2 types of inhibitory/regulatory receptors
Ctla4
Pd1
When is pd1 expressed
Can be expressed on activated T cells
(Not all the time, but can be)
What does pd1 bind
Binds pdl1 = expressed by many cells
And pdl2 = on apcs during inflammation
What does pd1 signalling do
Downregulates T cell activation/proliferation and function = make T cell unresponsive
What is pd1 marker of
T cell exhaustion
Occurs in chronic diseases
What are targets of some cancer therapies
Blocking pd1 or pdl1 or ctla4 = targets of some cancer therapies
Describe pd1 and ex of ctls
Normally = pdl1 binds pd1 = so then renders ctl unresponsive
Treatment =
Block pdl1 = anti pdl1
Or anti pd1 (block pd1 = not make unresponsive)
So then ctl can kill tumour cell
Cellular mechanisms of regulation
Tregs
iTreg pattern signal 3
Il2
Tfgbeta
iTreg Effector cytokines
Il10
Tgfbeta
(Anti inflammatory cytokines)
iTreg Master transcriptional regualtor
FoxP3
iTreg Functions
Suppress immune responses
= maintain immune tolerance to self antigens = prevent auto immunity
Prevent reaction to Safe non self or self
What does i in iTreg Mean
Induced = arise in lymph node
Signal 3 makes it treg
Where are natural tregs developed
Thymus derived
What is function of natural treg
Selected for high afffinity for self peptides —> dampen immune response to them
Regulate immune responses
What do natural tregs express
Express tcr, cd4, il2Ralpga, ctla4 - cannot provide il2 so rely on other cells (prevent overgrowth of T cells secreting il2)
Express foxp3
Where do induced- adaptive tregs arise
Arise in periphery from cd4+ T cells - activated by signal 3
What do induced adaptive tregs express
Express tcr, cd4, il2Ralpha, ctla4
Express foxp3 - some exceptions tho
iTreg tfs activated
Stat 5
What does iTreg secrete
Il10 and tgfbeta
iTreg What they do - gen
Represses other immune cells - mainly T cells
Prevent immune responses that are inappropriate - like autoimmune responses
(Functions for induced and natural tregs)
What do tregs do - gen
Negatively regulate immune responses
What do tregs do - deplete
Deplete local area of stimulating cytokines - express il2Ralpha (cd25) chain —> sequesters il2
What do tregs do - sequester
B7 sequestration by ctla4 = inhibit signal 2
Inhibit apc activity by reducing co stimulatory molecule expression and pro inflammatory cytokine secretion
= reduce T cell activation and differentiation
What do tregs do - produce
Immunosuppressive cytokines = il10 and tgfbeta
What do tregs do - directly
Directly kill T cells through granzymes and metabolic disruption
What does treg il10 do
Inhibit production of th1 and th17 cytokines
= inhibit their functions
What does treg tgfbeta do
Inhibit T cell proliferation and inhibit development and function of th1 and th2
What are T cells specific to
Peptides that are dangerous non self
What are tregs specific to - GEN
Specific to peptides that are self or Safe non self
= opposite!!!
What are tregs specific to - compare natural and induced tregs
Ntreg recognizes self peptide:Mhc —> arise in thymus
ITreg recognizes peptide:mhc (could be self or commensal ag) —> arise in periphery
What happens to autoreactive T cells
Majority are deleted in development process in cytokines
Some can escape and cause allergies or autoimmunity
Define tolerance
Preventing immune response against self proteins
What do tregs make sure of
Tregs make sure None of autoreactive T cells in circulation get activated
What happens if treg finds its match - specifically
If treg recognizes p:mhc on apc —> MUST MEAN apc is presenting self peptides
So then treg secretes cytokines that will inhibit neighbouring T cells (potentially auto reactive) that recognize other self peptides:mhc being presented by same cell from being activated
What happens if treg finds its match - informally
Like damps = cell debris, self tho, but apcs still express these
Lots of diff peptides presented on diff mhcs on surface apcs - but the peptides all come from same source - self protein
If cell apoptosis and dc takes up proteins —> present on mhc —> treg binds but notices other T cells binding = these are auto reactive
So treg secretes cytokines to stop these autoreactive T cells
